Method of treating hemorrhoids using macrocyclic lactone compound

ABSTRACT

A method of treating hemorrhoids is disclosed. The method includes locally administering a composition including an effective amount of one or more macrocyclic lactone compounds, including avermectin compounds, milbemycin compounds, or mixture thereof and a pharmaceutically acceptable carrier to the affected anorectal region of an individual suffering from hemorrhoid.

FIELD OF THE INVENTION

The present invention relates to a method of treating hemorrhoids, moreparticularly a method of treating hemorrhoids using one or moremacrocyclic lactone compounds, more specifically, one or more avermectincompounds or milbemycin compounds.

BACKGROUND OF THE INVENTION

Hemorrhoids are part of the normal human anatomy of the anal canal. Intheir physiological state they act as cushions composed ofarterio-venous channels and connective tissue that aid the passage ofstool. They become pathological or piles when swollen or inflamed.Hemorrhoids are classified according to their origin and the dentateline (pectinate line) serves as an anatomic border.

External hemorrhoids are dilations of anorectal vessels below thedentate line, which occur outside the anal verge (the distal end of theanal canal). Specifically, external hemorrhoids are varicosities of theveins draining the territory of the inferior rectal arteries, which arebranches of the internal pudendal artery. External hemorrhoids commonlypresent with pain in the area of anus and often accompanied by swellingand irritation. External hemorrhoids are prone to thrombosis. If thevein ruptures and/or a blood clot develops, the hemorrhoid becomes athrombosed hemorrhoid.

Internal hemorrhoids are dilations of anorectal vessels above thedentate line, which occur inside the rectum. Specifically, internalhemorrhoids are varicosities of veins draining the territory of branchesof the superior rectal arteries. As this area lacks pain receptors,internal hemorrhoids are usually not painful and many people are notaware that they have the condition. However, internal hemorrhoids maybleed when irritated and untreated internal hemorrhoids can lead to twosevere forms of hemorrhoids: prolapsed and strangulated hemorrhoids.Prolapsed hemorrhoids are internal hemorrhoids that are so distendedthat they are pushed outside the anus. If the anal sphincter muscle goesinto spasm and traps a prolapsed hemorrhoid outside the anal opening,the supply of blood is cut off, and the hemorrhoid becomes astrangulated hemorrhoid.

Some hemorrhoids are regarded as mixed hemorrhoids (internal-external),arising from the inferior and superior hemorrhoidal plexi and theiranastomotic connections, covered by mucosa in the superior part and skinin the inferior part, so they have somatic pain fibers.

Internal hemorrhoids are further classified into four grades accordingto the extent of prolapse. In first-degree hemorrhoids, the hemorrhoidaltissue protrudes into the lumen of the anal canal, but does not prolapseoutside the anal canal. The veins of the anal canal are increased insize and number and may bleed at the time of evacuation. Second-degreehemorrhoids may prolapse beyond the external sphincter and be visibleduring evacuation but spontaneously return to lie within the anal canal.Third-degree hemorrhoids protrude outside the anal canal and requiremanual reduction, and fourth-degree hemorrhoids are irreducible and areconstantly prolapsed.

A number of factors may lead to the formations of hemorrhoids, whichinclude irregular bowel habits (constipation or diarrhea), exercise,gravity, low-fiber diet, increased intra-abdominal pressure (prolongedstraining), pregnancy, obesity, prolonged sitting time, genetics,absence of valves within the hemorrhoidal veins, and aging.

Existing conservative treatments typically include life stylemodification, such as improving anal hygiene, increasing the intake ofdietary fiber and fluids in the diet, and avoiding constipation ordiarrhea, sitz baths, and rest; oral medication and topical treatment.In Europe and Asia, oral vasotopic drugs are used for treatinghemorrhoids. It has been reported recently that oral micronized,purified flavonoid fraction rapidly relieves hemorrhoidal bleeding.

Many over the counter topical treatment products are available forhemorrhoids, which include pads, topical ointments, creams, gels,lotions, and suppositories. These preparations may contain variousingredients such as local anesthetics, corticosteroids,vasoconstrictors, antiseptics, keratolytics, protectants (such asmineral oils, cocoa butter), astringents (ingredients that causecoagulation, such as witch hazel), and other ingredients. Topicalapplication of corticosteroids may ameliorate local perianalinflammation, however, long term use of high-potency corticosteroidcreams can cause permanent damage and thinning of the perianal skin.Local anesthetics, such as 5% lidocaine ointment, decrease permeabilityto sodium ions in neuronal membranes, resulting in inhibition ofdepolarization, blocking transmission of nerve impulses. Preparation H®,one of the world's best-selling hemorrhoid treatments, contains 0.25%phenylephrine, a drug which constricts blood vessels. Preparation H mayimprove local symptoms but does not treat the underlying disorder andlong term use is discouraged due to local irritation of the skin. Mostof these topical treatment products help the patient maintain personalhygiene, and may alleviate symptoms of pruritus and discomfort. Thereare no prospective randomized trials suggesting that they reducebleeding or prolapse.

Several nonsurgical procedures have been used to treat hemorrhoids,which function by ablation, sclerosis, or necrosis of mucosal tissues.These include rubber band ligation, sclerotherapy, and cauterization byusing electrocautery, infrared radiation, or cryosurgery. Whenconservative medical management fails, surgeries have been used to treatsevere hemorrhoids, for example, hemorrhoidectomy, doppler guidedtransanal hemorrhoidal dearterialization, and stapled hemorrhoidectomy.However, all surgical treatments are associated with some degree ofcomplications, including bleeding, infection, anal strictures, andurinary retention due to the close proximity to the rectum of the nervesthat supply the bladder.

The macrocyclic lactones (avermectins and milbemycins) are products orchemical derivatives thereof, of soil microorganisms belonging to thegenus Streptomyces. The avermectin series and milbemycin series ofcompounds are very potent antiparasitic agents, useful against a broadspectrum of endoparasites and ectoparasites in mammals and also havingagricultural utilities against various nematode and insect parasitesfound in and on crops and in soil. Compounds of this group includeavermectins, milbemycins, and their semi-synthetic derivatives, forexample, ivermectin, doramectin, emamectin, eprinomectin, selamectin,latidectin, milbemectin, moxidectin, nemadectin, milbemycin oxime, andlepimectin. These chemicals have been described, for example, in U.S.Pat. Nos. 3,950,360, 4,199,569, 4,879,749 and 5,268,710. The avermectinsand, to a lesser extent, the milbemycins, have revolutionizedantiparasitic and antipest control over the past few decades.

In terms of their mechanism of action as antiparasitic agents, theavermectins block the transmittance of electrical activity in nerves andmuscle cells by activating voltage dependent membrane-bound proteinscontaining chloride channels. Chloride channel blockers in both insectsand mammals are highly toxic convulsants causing a hyperexcitation ofthe nervous system through antagonism of the inhibitory neurotransmitterGABA. Avermectin compounds effectively block GABA stimulated uptake andcause a release of chloride-channel dependent neurotransmitters.Milbemycin compounds have a similar mechanism of action, but a longerhalf-life than the avermectins. Milbemycin compounds open glutamatesensitive chloride channels in neurons and myocytes of invertebrates,leading to hyperpolarization of these cells and blocking of signaltransfer.

Ivermectin has been used as an antiparasitic agent to treat variousanimal parasites and parasitic diseases since mid-1980's. It iscommercially available for animal use as Cardomec™ (for felines),Zimecterin® (for equines) and Ivomec® (for bovines) by MERIAL Limited,Duluth, Ga. The medicine is available in tablets, paste, or chewablesfor heartworm prevention, topical solution for ear mite treatment, or asoral or injectable solution for other parasite problems.

Ivermectin is also commercially available from Merck & Co., Inc forhuman use as Stromectol® for eradication of threadworm Strongyloidesstercoralis, and for eradication of Onchocerca volvulus. The medicine isavailable in tablets and is orally administered by the patients. Magdaet al. (Amer. J. Trop. Med. Hyg. 53(6) 1995 pp. 652-653) describe amethod of topical application of ivermectin to treat head lice. U.S.Pat. No. 5,952,372 (to McDaniel) discloses a method of treating a formof rosacea associated with the ectoparasite Demodex by eliminatingmites.

Recently, ivermectin has also been found useful in treatingdermatological conditions. U.S. Pat. Nos. 6,133,310, 6,433,006,6,399,652, 6,399,651 and 6,319,945 (to Parks) disclose methods oftreating acne rosacea, seborrheic dermatitis, acne vulgaris, transientacantholytic dermatitis, acne miliaris necrotica, acne varioliformis,perioral dermatitis, and acneiform eruptions by topically applying anavermectin compound, particularly ivermectin, to the affected areas.

Hemorrhoids are a common public health problem. Symptomatic hemorrhoidsaffect at least 50% of the American population at some time during theirlives, with about 5% of the population suffering at any given time.Moreover, the existing topical medications for treating hemorrhoids havelimited effects. Therefore, there is a need for more effective andimproved topical compositions and minimal invasive methods for treatinghemorrhoids.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is directed to a method oftreating hemorrhoid. The method comprises locally administering acomposition comprising an effective amount of one or more macrocycliclactone compounds including avermectin compounds, milbemycin compounds,or mixture thereof and a pharmaceutically acceptable carrier to theaffected region of an individual suffering from hemorrhoid. Thecomposition is administered intrarectally or topically to the anal vergeand perianal skin of the individual one or more times.

In another embodiment, the present invention is directed to acomposition comprising one or more avermectin compounds, milbemycincompounds, or mixtures thereof for treating hemorrhoid.

The avermectin compounds in the hemorrhoidal composition includeavermectins, or avermectin derivatives such as ivermectin, ivermectinderivatives, emamectin, doramectin, selamectin, eprinomectin, orlatidectin. The milbemycin compounds include milbemycins, or milbemycinderivatives such as moxidectin, nemadectin, milbemycin oxime, orlepimectin. Preferably, the hemorrhoidal composition comprises aneffective amount of ivermectin.

The advantages of the present invention will become apparent from thefollowing description in conjunction with exemplary embodiments of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a method of treatinghemorrhoid using one or more macrocyclic lactone compounds. The methodcomprises locally administering a hemorrhoidal composition comprising aneffective amount of one or more macrocyclic lactone compounds includingavermectin compounds, milbemycin compounds, or mixture thereof and apharmaceutically acceptable carrier to the affected anorectal region ofan individual suffering from hemorrhoid.

In another embodiment, the present invention provides the use of one ormore macrocyclic lactone compounds including avermectin compounds,milbemycin compounds, or mixture thereof in the preparation of apharmaceutical composition intended for the treatment of hemorrhoid.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one having ordinaryskills in the art to which the invention belongs.

The macrocyclic lactone compounds for the purpose of the presentinvention include avermectin compounds and milbemycin compounds. Theavermectin compounds for the purpose of the present invention includeavermectins and derivatives thereof, which include, but not limited to,avermectin A_(1a), A_(1b), A_(2a), A_(2b), B_(1a), B_(1b), B_(2a), orB_(2b), ivermectin and derivatives thereof, emamectin, doramectin,selamectin, eprinomectin, latidectin, or mixtures thereof. Themilbemycin compounds for the purpose of the present invention includemilbemycins and derivatives thereof, which include, but not limited to,milbemycins, moxidectin, nemadectin, milbemycin oxime, milbemectin,lepimectin, or mixtures thereof.

In one embodiment, the hemorrhoidal composition comprises one or moreavermectin compounds and a pharmaceutically acceptable carrier or amedium which is suitable for application to the affected anorectalregion, as described further in detail hereinafter. In anotherembodiment, the hemorrhoidal composition comprises one or moremilbemycin compounds and a pharmaceutically acceptable carrier or amedium which is suitable for application to the affected anorectalregion. Preferably, ivermectin is used in the hemorrhoidal composition.

The following molecular structure represents avermectins, which can bechemically converted to useful derivatives as discussed below.

wherein the broken line at the 22-23 position represents an optionaldouble bond; R₁ is hydroxy and is present only when the bond at the22-23 position is a single bond; R₂ is isopropyl or sec-butyl; R₃ ismethoxy or hydroxyl, and R is the4′-(alpha-L-oleandrosyl)-alpha-L-oleandroside of the structure:

The naturally occurring avermectins are a series of 16-memberedmacrocyclic lactones isolated from fermentation products of Streptomycesavermitilis, a soil Actinomycete. There are eight different but closelyrelated compounds produced by Streptomyces avermitillis, isolated infour pairs of homologue compounds with a major (a-component) and a minor(b-component) component, which are designated as avermectin A_(1a),A_(1b), A_(2a), A_(2b), B_(1a), B_(2b), B_(2a), and B_(2b). The mixtureof avermectin B_(1a) and B_(1b), widely used insecticide andantihelmintic, are commonly referred to as abamectin. The production ofthese compounds is described in U.S. Pat. No. 4,310,519, which isincorporated herein by reference in its entirety. The structures ofthese eight individual compounds in reference to the above structuralformula have been identified as follows:

R₁ R₂ R₃ A_(1a) Double bond sec-butyl —OCH₃ A_(1b) Double bondiso-propyl —OCH₃ A_(2a) —OH sec-butyl —OCH₃ A_(2b) —OH iso-propyl —OCH₃B_(1a) Double bond sec-butyl —OH B_(1b) Double bond iso-propyl —OHB_(2a) —OH sec-butyl —OH B_(2b) —OH iso-propyl —OH

The 22, 23-double bond of some avermectins may be selectively reduced toprepare ivermectin and its derivatives. Ivermectin, a member ofavermectin compounds, is a semi-synthetic derivative of avermectins andis generally produced as a mixture of 22,23-dihydroavermectin B_(1a) and22,23-dihydroavermectin B_(1b). The preparation of ivermectin andderivatives are disclosed in U.S. Pat. No. 4,199,569, which isincorporated herein by reference in its entirety.

The following structural formula shows the structures of ivermectin andits derivatives:

wherein R₁ is iso-propyl or sec-butyl; R₂ is methoxy, hydroxy oralkanoyloxy; R₃ is hydrogen; alkanoyl; alpha-L-oleandrosyl;4′-alkanoyl-alpha-L-oleandrosyl;4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosyl; or4″-alkanoyl-4′-(alpha-L-oleandrosyl)-alpha-L-oleandrosyl. Herein, the“alkanoyl” includes alkanoyl groups having 2 to 6 carbon atoms such asacetyl, propionyl, butyryl, and pivaloyl. Ivermectin and its derivativesshown above share profound anthelmintic, insecticidal, ectoparasiticidaland acaricidal activities.

Doramectin and eprinomectin are represented by the following structure:

In doramectin, x=x is —CH═CH—; R₁ is —C₆H₁₀; R₂ is —OH. In eprinomectin,x=x is —CH═CH—; R₁ is —CH(CH₃)CH₂CH₃, or —CH(CH₃)₂; R₂ is —NHCOCH₃.These compounds are described in “Veterinary Parasitology”, vol. 49, No.1, July 1993, 5-15.

Selamectin has the following structure:

which is described in EP1142577A2 and WO 94/15944.

Emamectin has the following structure:

where R is —CH₂CH₂ or —CH₃. Emamectin and its salts are described inU.S. Pat. Nos. 4,874,749 or 5,288,710.

The structure of latidectin, which is a mixture of components A3 and A4,is shown below:

where component A3 has R=—CH₂CH₃, and component A4 has R=—CH₃.

Other avermectin derivatives are also known in the art. For example, theavermectins possess a disaccharide moiety at the C-13 positionconsisting of the alpha-L-oleandrosyl-alpha-L-oleandrosyl group. One orboth of these saccharide groups may be removed as described in U.S. Pat.No. 4,206,205, and the produced aglycone derivatives have a hydroxygroup at the 13-position. This group may be removed to form the 13-deoxycompound as described in U.S. Pat. Nos. 4,171,314 and 4,173,571, and thelatter patent also describes the 13-halo derivatives. U.S. Pat. No.5,077,308 describes avermectin aglycone derivatives which incorporate aketal at C-13 position. The avermectins and derivatives have severalhydroxy groups which may be acylated as described in U.S. Pat. Nos.4,201,861. 5,055,454 describes avermectin derivatives in which position13 of avermectin has been inverted from a normal alpha stereochemistryto the epimeric C-13 beta stereochemistry. U.S. Pat. No. 5,162,363describes avermectin derivatives where the 23-position ring carbon atomis replaced with sulfur atom. U.S. Pat. No. 5,229,416 describesavermectin aglycone derivatives which incorporate two fluorine atoms atposition 13 and 23. U.S. Pat. No. 5,262,400 describes avermectincompounds that have various substituents at the 4a-position includingalkyl, alkoxy alkyl, or polyalkoxy alkyl groups. Other derivatives ofavermectin and ivermectin are disclosed in U.S. Pat. Nos. 4,333,925,4,963,667, 5,114,930, 5,350,742, and 5,830,875. All aforementionedpatents are incorporated herein by reference in their entirety.

All ivermectin compounds mentioned above share the 16-memberedmacrocyclic lactone ring and the spectrum of anti-parasitic biologicalactivity of ivermectin, varying only in degree. It is expected that theyalso share the activity spectrum of ivermectin suitable for the purposeof the present invention.

Like avermectins, milbemycins are products of fermentation byStreptomyces species, isolated from the fermentation broth ofStreptomyces hygroscopicus subsp. aureolacrimosus. They have same modeof action, but a longer half-life than the avermectins. Milbemycinsinclude a series and β series, which were initially named as B-41antibiotics and given the designation A₁, A₂, A₃, A₄, B₁, B₂, B₃, C₁ andC₂, as described in U.S. Pat. Nos. 3,950,360 and 3,984,564. The B-41designations are still commonly used today. The correlation of theinitial designation to the nomenclature of α and β series of somemilbemycins is described in U.S. Pat. No. 4,144,352. Within the family,milbemycins α₁₁, α₁₄, A₃ and A₄ have been found having the mosteffective acaricidal activity. A mixture of milbemycins A₃ and A₄ iscommercialized under the name milbemectin.

The following structural formula represents milbemectin and severalpotent derivatives of milbemycins:

R₁ R₂ R₃ Milbemectin —H, —H, —H —CH₃; —CH₂CH₃ (β)-OH Milbemycin ═NOH —H,—H —CH₃; —CH₂CH₃ oxime Moxidectin —H, ═NOCH₃ (Z)—C(CH₃)═CH—CH(CH₃)₂(β)-OH Nemadectin —H, —H, (Z)—C(CH₃)═CH—CH(CH₃)₂ (β)-OH (α)-OH

Further description of milbemycins and their derivatives can be found in“Avermectins and Milbemycins”, Davies H. G. et al., 1986, Nat. Prod.Rep., 3, 87-121; “Synthesis of Milbemycins from Avermectins”, Mrozik H.et al., 1983, Tetrahedron Lett., 24, 5333-5336; and U.S. Pat. Nos.4,134,973 and 4,144,352.

A further derivative of milbemycin is lepimectin, which has thefollowing structure:

where R is —CH₂CH₃ (major component), and R is —CH₃ (minor component).

Both avermectins and milbemycins have macrocyclic lactone structuresthat are superimposable, they are produced by the same genus of soildwelling organisms, they have the same mode of action, and they exertthis action against the same nematode/acarine/insect spectrum oftargets. It is expected that milbemycin compounds also share theactivity spectrum of ivermectin suitable for the purpose of the presentinvention.

The concentration of the one or more avermectin compounds or the one ormore milbemycin compounds in the hemorrhoidal composition for thepurpose of the present invention can be greater than 0.001% weight byweight (w/w). In some embodiments, the concentration of the one or moreavermectin compounds or the one or more milbemycin compounds in thecomposition is in a range from about 0.001% to about 10% (w/w),preferably from about 0.03% to about 5% (w/w), and more preferably fromabout 0.05% to about 3% (w/w). In a preferred embodiment, ivermectin isused. The concentration of ivermectin in the composition can be greaterthan 0.001% (w/w). In some embodiments, the concentration of ivermectinin the hemorrhoidal composition is from about 0.001% to about 10% (w/w),preferably from about 0.03% to about 5% (w/w), and more preferably fromabout 0.05% to about 3% (w/w). It has been found that the hemorrhoidalcomposition containing ivermectin at a concentration as low as 0.075% iseffective, as illustrated in the examples hereinafter, in treatinghemorrhoid. Such a low effective concentration is advantageous becauseit reduces risks of side effects and the possibility of triggeringbody's autoimmune responses.

Pharmaceutically acceptable carriers or media suitable for topicalapplication to anorectal region are known to those having ordinary skillin the art. The hemorrhoidal composition can be in various forms,including, but not limited to, suppository, solution, spray, gel,ointment, or emulsion in the form of liquid suspension, lotion, orcream. The hemorrhoidal composition can also be integrated into medicaldressing or toilet wipes. Furthermore, the hemorrhoidal composition canalso be in the form of suspensions of microspheres or nanospheres, lipidor polymeric vesicles, or polymeric patches or hydrogels for controlledrelease.

In some embodiments, the hemorrhoidal composition is in the form ofsuppository. Typically, suppository includes one or more lipophilicagents. Suitable examples of lipophilic agents include, but not limitedto, hydrogenated vegetable oils, cocoa butter, glycerinated gelatin,polyethylene glycols of different molecular weights, and fatty acidesters of polyethylene glycols. A suppository is placed in the rectalcanal by inserting the suppository in a hardened state into the anus.The suppository is advanced past the anal sphincter where it is retainedin the rectum of the patient. As the suppository is heated by the body,it melts and the macrocyclic lactone compound is released from thesuppository to the surrounding mucosal tissue.

The mucosal tissue is an ideal site for the macrocyclic lactone compoundto be delivered locally, because mucosal tissue has a very thinepithelium with minimal keratinized tissue, therefore, does not hinderthe transport of the active component as compared to normal epidermalskin containing thick layers of keratinized tissues. Moreover, mucosaltissue is exposed to an abundant blood supply, which facilitateseffective delivery into the hemorrhoids and the surrounding tissue.

In one exemplary embodiment, the hemorrhoidal composition is in a formof lotion having substantially neutral pH from about 6 to about 7.Example 1 provides an exemplary hemorrhoidal composition comprisingivermectin in a lotion. As shown in the example, a commerciallyavailable moisturizing lotion manufactured by Galderma Laboratories,Inc. under the trade name Cetaphil® moisturizing lotion is used as themedium for ivermectin to form the hemorrhoidal composition. Cetaphil®moisturizing lotion contains purified water, glycerin, hydrogenatedpolyisobutene, cetearyl alcohol and ceteareth-20, macadamia nut oil,dimethicone, tocopheryl acetate, stearoxytrimethylsilane and stearylalcohol, panthenol, farnesol, benzyl alcohol, phenoxyethanol,acrylates/C10-30 alkyl acrylate crosspolymer, sodium hydroxide, andcitric acid.

In some embodiments, the hemorrhoidal composition is an emulsion withone or more macrocyclic lactone compound therein. More specifically, thehemorrhoidal composition comprises one or more avermectin compound ormilbemycin compound, one or more solvents for the active agent, an oilyphase, one or more surfactants as emulsifier, and water. The method ofpreparing an emulsion is known to those skilled in the art. The emulsioncan be formulated into a solution, lotion, or cream. The emulsion canalso be sprayable. Example 2 provides an exemplary hemorrhoidalcomposition, which is a cream containing 1% of ivermectin.

The hemorrhoidal composition in the form of ointments can be preparedusing either an oleaginous base or medium or an absorbent base. Theoleaginous base comprises fixed oils or hydrocarbons, such as whitepetrolatum or mineral oil. The absorbent base comprises an anhydroussubstance or substances which can absorb water, for example anhydrouslanolin. Following formation of the base, the macrocyclic lactonecompound is added to an amount affording the desired concentration toform the hemorrhoidal composition.

In some embodiments, the composition is in the form of a hydrogel. Thewater content in the gel has hydrating and cooling effect of theinflamed tissue. In some embodiments, the composition is in the form ofliquid. The hemorrhoidal composition in the liquid form can be packagedinto a squeezable liquid medicine dispenser with a rectal nozzle, suchas an enema bottle.

The hemorrhoidal composition of the present invention described above isadministered locally to the affected anorectal region, which includesadministering intrarectally and/or administering topically to the analverge and perianal skin. The phrase “administering intrarectally” usedherein means administering into the rectum and anal canal, also referredto as anorectal canal. The term “anorectal region” used herein refers tothe rectum and anal canal, the anal verge and the perianal skin.

In addition to the delivery of suppository and liquid compositiondescribed above, the hemorrhoidal composition in the form of lotion,cream, gel, or ointment can be instilled into the anorectal canal andapplied topically to the anal verge and perianal skin with a glovedfinger by the patient or using other tools that facilitate intrarectaldelivery, for example cannula or nozzle. For external hemorrhoids,toilet wipes or medical dressing integrating the hemorrhoidalcomposition can also be conveniently used by the patient or medicalprofessionals as needed.

The hemorrhoidal composition can be administered to the affectedanorectal region one or more times a day, typically one to two times aday, when a pathological hemorrhoid condition occurs. When severe painand swelling are present, the hemorrhoidal composition can beadministered more frequently. It has been discovered by the inventorsthat application of the hemorrhoidal composition containing ivermectinto the anorectal region is effective in treating hemorrhoid,particularly at the early onset of the condition. A rapid resolution ofthe symptoms of hemorrhoids with only one or two application of anivermectin lotion described in the examples to the affected region hasbeen observed with many patients. Typically, the pain, swelling andirritation subside significantly within 24 hours after the application.

Preferably, the hemorrhoidal composition is administered to the affectedanorectal region at early onset or prodrome of hemorrhoid. In medicine,a prodrome is an early symptom (or set of symptoms) that might indicatethe start of a disease before specific symptoms occur. Prodromes may benon-specific symptoms or, in some instances, may clearly indicate aparticular disease. In hemorrhoids, there is a prodrome involving avague feeling of discomfort at the anorectal region, which may betriggered by early inflammation and tissue swelling. Typically, after afew episodes, a patient can recognize such feeling as indicating animpending recurrence of hemorrhoids. It has been found that if thehemorrhoidal composition containing ivermectin is applied at the timethe patient recognizes the prodrome of hemorrhoid, only one applicationis sufficient to prevent a full blown episode of pathological hemorrhoidcondition. In many instances, no further application or other treatmentsis needed after one single application of the instant hemorrhoidalcomposition. Such efficiency in the treatment of hemorrhoids isunexpected.

Examples 3 through 6 illustrate the effectiveness of the method of thepresent invention in treating hemorrhoid. As shown, after the patientssuffering from internal or external hemorrhoids were treated with theinstant hemorrhoidal composition containing 0.075% of ivermectin, arapid resolution of the symptoms of pain, swelling, and irritation wastypically observed within 24 to 48 hours.

Without being bound by any theoretical explanation and based on clinicalobservations by the inventors, it is believed that the efficacy of thehemorrhoidal composition and the method of the present invention intreating hemorrhoids is due in part to the anti-inflammatory property ofivermectin, as well as its antiseptic properties. It is believed thativermectin is an effective anti-inflammatory agent, which blocks certainmediators of inflammation, therefore, diminishes symptoms caused byinflammation. This is substantially different from many existinghemorrhoidal medications, which merely treat the symptoms, but not theroot cause, namely inflammation. Moreover, in view of the effect ofivermectin on neural system, it may also have some direct effects on theneural receptors in the anorectal region, which may contribute to therapid pain relief observed clinically.

The hemorrhoidal composition containing ivermectin can be provided as akit wherein the composition is packaged in a container. Instructions onhow to use the hemorrhoidal composition in accordance with the presentinvention are included on or associated with the container, whichprovides detailed instructions for treating hemorrhoids. Optionally, thekit can further include application tools, such as disposable rectalnozzles, or finger cot gloves.

The following examples are illustrative of the invention and are in noway to be interpreted as limiting the scope of the invention, as definedin the claims. It will be understood that various other ingredients andproportions may be employed, in accordance with the proceedingdisclosure.

EXAMPLE 1

Composition A of an ivermectin lotion is prepared as follows: mix 0.04 gof Zimecterin® (manufactured by MERIAL Limited, Duluth, Ga.) whichcontains 1.87% ivermectin, sufficiently with 100 mg of Cetaphil®moisturizing lotion (manufactured by Galderma Laboratories, Inc.) toform an ivermectin lotion. The ivermectin concentration in the formedlotion is 0.075% (w/w).

Composition B of an ivermectin lotion is prepared as follows: mix 0.054g of Zimecterin® containing 1.87% ivermectin sufficiently with 100 mg ofCetaphil® moisturizing lotion to form an ivermectin lotion. Theivermectin concentration in the formed lotion is 0.1% (w/w).

Other suitable compositions that can be made in accordance with Example1 include ivermectin in the following concentrations: 0.01%, 0.05%,0.12%, 0.15%, 0.2%, 0.5%, 1%, and 2% (w/w) with Cetaphil® moisturizinglotion as a medium. Other compatible commercial available lotions canalso be used as a medium or carrier.

EXAMPLE 2

The following emulsion is prepared with the method known in the art.

Ingredients Percentage (% w/w) Ivermectin 1.0 Glycerol 4.0 AcrylateC10-30 alkyl acrylate crosspolymer 0.2 Methyl para-hydroxybenzoate 0.2Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate 4.0Cetyl alcohol 3.5 Stearyl alcohol 2.5 Oleyl alcohol 2.0 Ceteareth-20 3.0Sorbitan monostearate 2.0 Dimethicone 200 20 cs 0.5 Propylpara-hydroxybenzoate 0.1 Propylene glycol 2.0 Phenoxyethanol 1.0 10%sodium hydroxide qs pH to 6.3 Water qs 100

The emulsion is in the form of cream.

Operating with informed consent of individuals, individuals were treatedwith the hemorrhoidal composition and the method of the presentinvention for treating hemorrhoids, as described in Examples 3 to 6.

EXAMPLE 3

A 70-year old male, while serving in the army at age of 30, developed ared, hot clotted, internal/external hemorrhoid after strenuous exercise.The lesion had to be incised to evacuate the clot, and healing occurredover several days. However, since then the patient has had recurrentepisodes of small internal and external hemorrhoids associated with anacute pain in the rectal vault. The patient was initially treated withComposition A of the ivermectin lotion of Example 1 when an acuteepisode occurred. The ivermectin lotion was applied intrarectally andaround anus using a gloved finger. The treatment resulted in promptrelief of pain and the lesions subsided in one to two days. The patientlearned to recognize the vague uncomfortable prodrome as an impending,inflamed hemorrhoid, then immediately applied the lotion. The discomfortcleared overnight, usually requiring only one dose. After the treatmentwith the ivermectin lotion for several episodes occurred in a period ofmore than two years, the patient reports now that the frequency ofattacks has decreased in comparison to the historical recurrent patternprior to using the ivermectin treatment.

EXAMPLE 4

A 50-year old white female with a long history of internal and externalhemorrhoids since childbirth in 1987. None of the prior therapies hadbeen satisfactory. A sample of Composition A of the ivermectin lotion ofExample 1 was provided to the patient with instruction of applyingintrarectally and externally to the affected region. The patientreported prompt resolution of the symptoms of pain and irritation in 48hours after application of the ivermectin lotion twice a day in arecurrent episode. Moreover, the patient was pleased that the lotion wasnot as messy as existing commercial products.

EXAMPLE 5

A 48-year old male physician was seen with recurrent hemorrhoids, whichwas poorly responsive to standard treatments with over the counter andprescription topical medications (steroids and anti-inflammatorymedications). The patient was given a trial of Composition A of theivermectin lotion of Example 1 to instill high into the rectal vault. Aprompt relief of the symptoms was observed in two hours and the patientwas amazed with the effect of the treatment. A sample of the ivermectinlotion was provided to the patient for home use twice a day forrecurrent episodes.

EXAMPLE 6

A 24-year old white female with a long history of small, painful,internal rectal vault hemorrhoids with occasional anal rim hemorrhoids.The patient was treated with topical application of Composition B of theivermectin lotion of Example 1 to the affected region twice a day. Thetreatment provided prompt pain relief and dissipation of the hemorrhoidsin 24 to 48 hours. Subsequently, the patient was taught to recognize thesigns of impending recurrence and to treat promptly for effectiveself-management of the chronic condition. In follow ups with thepatient, the patient noted that since following the instruction ofprompt application of the ivermectin lotion at the time of recognizingthe prodrome, the frequency of hemorrhoid has decreased dramatically.

In the above described informal trials, no adverse side effects orcontra-indications were observed among the patients. The patients had nocomplaints of irritation, sensitivity or discomfort at the appliedregions originating from the treatment.

Each patent, patent application, publication, text and literaturearticle or report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While there has been shown and described the preferred embodiment of theinstant invention it is to be appreciated that the invention may beembodied otherwise than is herein specifically shown and described andthat, within said embodiment, certain changes may be made in the formand arrangement of the parts without departing from the underlying ideasor principles of this invention as set forth in the Claims appendedherewith.

What is claimed is:
 1. A method of treating hemorrhoid comprisinglocally administering an effective amount of one or more macrocycliclactone compound to affected region of an individual suffering fromhemorrhoid, wherein said macrocyclic lactone compound is avermectincompound, milbemycin compound, or mixtures thereof.
 2. The method ofclaim 1, wherein said macrocyclic lactone compound is administeredintrarectally to the individual.
 3. The method of claim 1, wherein saidmacrocyclic lactone compound is administered topically to the anal vergeand the perianal skin to the individual.
 4. The method of claim 1,wherein said macrocyclic lactone compound is applied with a glovedfinger or using a nozzle.
 5. The method of claim 1, wherein saidmacrocyclic lactone compound is administered one to more times a day tothe affected region.
 6. The method of claim 1, wherein said hemorrhoidis an internal or external hemorrhoid.
 7. The method of claim 1, whereinsaid avermectin compound is selected from the group consisting ofavermectins, ivermectin, emamectin, doramectin, selamectin,eprinomectin, and latidectin.
 8. The method of claim 1, wherein saidmilbemycin compound is selected from the group consisting ofmilbemycins, moxidectin, nemadectin, milbemycin oxime, milbemectin, andlepimectin.
 9. The method of claim 1, wherein said macrocyclic lactonecompound is from about 0.001% to about 10% (w/w) in a composition. 10.The method of claim 1, wherein said macrocyclic lactone compound is fromabout 0.03% to about 5% (w/w) in a composition.
 11. The method of claim1, wherein said macrocyclic lactone compound is from about 0.05% toabout 3% (w/w) in a composition.
 12. The method of claim 1, wherein saidavermectin compound is ivermectin.
 13. The method of claim 12, whereinsaid ivermectin is greater than 0.001% (w/w) in a composition.
 14. Themethod of claim 12, wherein said ivermectin is from about 0.001% toabout 10% (w/w) in a composition.
 15. The method of claim 1, whereinsaid macrocyclic lactone compound is in a suppository.
 16. The method ofclaim 1, wherein said macrocyclic lactone compound is in a lotion,cream, gel, solution, ointment, or spray.
 17. The method of claim 1,wherein said macrocyclic lactone compound is integrated in a medicaldressing or toilet wipes.
 18. The method of claim 1, wherein applyingsaid macrocyclic lactone compound to the affected area rapidly relievespain, swelling and irritation associated with the hemorrhoid, and/ordissipates the hemorrhoid.
 19. The method of claim 18, wherein applyingsaid macrocyclic lactone compound to the affected area relieves pain,swelling and irritation associated with the hemorrhoid, and/ordissipates the hemorrhoid within 24 to 48 hours.
 20. The method of claim1, wherein applying said macrocyclic lactone compound to the affectedarea decreases frequency of reoccurrence of the hemorrhoid.
 21. Themethod of claim 1, wherein applying said macrocyclic lactone compound tothe affected area at prodrome of the hemorrhoid prevents a full blownepisode of pathological hemorrhoid condition.